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He is currently Head of the Medicine and Reproductive Biology department at the Centre Hospitalier de l'Université de Montréal (CHUM). He is one of the co-founders of the ovo clinic where he serves as medical director of ovo labo and ovo r&d. Dr Kadoch has completed his medical studies at the Faculty of Medicine at the University of Pierre and Marie Curie in Paris. Then, he completed a fellowship in reproductive endocrinology and infertility at the University of Montreal. He was the director of the university program of Gynecologic Reproductive Endocrinology and Infertility (GREI) and he is a committee member for examinations for the Royal College of Physicians and Surgeons of Canada in GREI.

Clinical failures of the highly active antiretroviral therapy could result from inefficient intracellular concentrations of antiviral drugs. The determination of drug contents in target cells of each patient would be useful in clinical investigations and trials. The purpose of this work was to quantify the intracellular concentration of ddATP, the active metabolite of dideoxyinosine (ddI), in peripheral blood mononuclear cells (PBMCs) of human immunodeficiency virus (HIV)-infected patients treated with ddI. We have raised antibodies against ddA-citrate, a stable isostere of ddATP selected on the basis of its structural and electronic analogies with ddATP. The anti-ddA-citrate antibodies recognized ddATP and ddA with nanomolar affinities and cross-reacted neither with any of the nucleotide reverse transcriptase inhibitors used in HIV therapy nor with their phosphorylated metabolites. The three phosphorylated metabolites of ddI (ddAMP, ddADP, and ddATP) were purified by anion exchange chromatography and the amount of each metabolite was determined by radioimmunoassay with or without prior phosphatase treatment. The intracellular levels of the three ddI metabolites were measured both in an in vitro model and in PBMCs of HIV-infected patients under ddI treatment. The possibility to measure intracellular levels of ddATP from small blood samples of HIV-infected patients treated with ddI could be exploited to develop individual therapeutic monitoring.Highly active antiretroviral therapy has been used successfully for treatment of human immunodeficiency virus (HIV) disease. The most common highly active antiretroviral therapy regimens consist of a combination of at least one protease inhibitor and two nucleoside reverse transcriptase inhibitors. Contrary to protease inhibitors, the expression of nucleoside reverse transcriptase inhibitor activity requires intracellular metabolism of the nucleoside precursor into its corresponding 5Ј-triphosphate nucleotide by the host cell kinases. The active metabolite (nucleoside reverse transcriptase inhibitor-triphosphate) competitively inhibits the HIV reverse transcriptase and acts as a chain terminator of the proviral DNA.The presence and activity of the intracellular kinases are highly dependent on the type and activation state of the target cell (37). Studies conducted in HIV-infected patients failed to establish a clear relationship between the plasma nucleoside reverse transcriptase inhibitor concentration and the antiviral efficiency of these drugs (3, 4, 18, 39). However, a clinical study showed a significant and linear relationship between the intracellular nucleoside reverse transcriptase inhibitor-triphosphate (zidovudine-triphosphate and lamivudine-triphosphate) concentrations, the percent change in CD4 ϩ cells and the rate of decline of HIV RNA in plasma (17). Thus, intracellular contents of active drugs in target cells seem to give a much better indication of therapeutic efficiency than plasma concentrations of drug precursors.The intracellular metabolism of ddI leads...

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